We spoke with Mark Yarchoan, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, about his recent study investigating the potential of a personalized therapeutic cancer vaccine in patients with advanced hepatocellular carcinoma (HCC).
Dr. Yarchoan details neoantigen-specific T cell responses assessed in the study as well as the clinical implications of the observed objective response rate.
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Can you explain how personalized therapeutic cancer vaccines operate and describe their potential role in enhancing responses to PD-1 inhibitors in hepatocellular carcinoma?
Dr. Yarchoan: It requires personalization. The way that this works is patients undergo a biopsy. That biopsy is then sent for sequencing to identify the mutations in the cancer. Once all the mutations in the cancer are identified, there is some sort of prioritization to figure out computationally which mutations are the most likely to result in a neoantigen that can be recognized by the immune system, so which have the most immunogenic potential. Then from that information, a vaccine is manufactured for an individual patient, targeting multiple suspected neoantigens within that tumor.
Please explain the design and methodology of your analysis. Why were safety and immunogenicity chosen as the primary end points?
Dr. Yarchoan: It was a multicenter trial. The sponsor was Geneos Therapeutics, which is a vaccine company. They have a DNA-based vaccine platform that is given with IL-12 as an adjuvant. This was the first time that a personalized vaccine was ever tested in HCC targeting multiple neoantigens with PD-1. It was also the first time this particular platform was used as a personalized cancer vaccine in a perspective clinical trial. There were a lot of firsts, and so this was, at the end of the day, a first in human clinical trial. Patients with advanced HCC who were on the approved first-line regimen, which was sorafenib or lenvatinib, underwent a biopsy and then a personalized vaccine was manufactured for the patient and so when the patient progressed on first-line therapy they became eligible to start treatment with this personalized vaccine in combination with pembrolizumab, the anti-PD-1 therapy.
How were neoantigen-specific T cell responses assessed in the study, and what were the key findings regarding the immunogenicity of the vaccine?
Dr. Yarchoan: Patients gave blood at various timepoints, and I think the key question was whether the vaccine actually induced anti-tumor immunity through induction of neoantigen specific responses. Using an ELISpot assay the majority of patients amounted an immune response against at least 1 neoantigen in the vaccine. There was clear induction of neoadjuvant specific immunity with the therapy.
Can you discuss the clinical implications of the observed objective response rate and complete response rate in patients receiving PTCV plus pembrolizumab?
Dr. Yarchoan: Anti-PD-1 therapy has been studied, and there have been multiple studies in HCC including multiple phase 3 studies. The response rate has been actually surprisingly consistent at a range of around 14% to 18%, depending on the study that you look at, and these include phase 3 studies of nivolumab, pembrolizumab, and other agents as well. We are fairly confident with the PD-1 response rate in this disease with a relatively narrow confidence interval. Although the primary end point of the study was safety and immunogenicity, we were also interested to see if there was a hint of efficacy. Was the response rate to the combination of the vaccine plus PD-1 was higher than would have been anticipated from the PD-1 agent alone? The null hypothesis would have been a response rate of 14% to 18%. This was a relatively small, phase 2 study, so it is important to put a number of caveats in there, but the response rate was around 31% which is clearly higher than has been seen with PD-1 monotherapy. It is certainly encouraging that the vaccine added efficacy in the advanced second line setting on top of anti-PD-1 therapy.
What further research, if any, do you believe is necessary regarding PTCVs and pembrolizumab for patients with HCC?
Dr. Yarchoan: The key takeaway from our study is that a personalized vaccine is feasible for HCC and at least initially seems to be associated with both efficacy and immunological efforts consistent with the efficacy observed. We won’t know for sure that this approach actually if efficacious until we do a randomized prospective trial. That really is the next step. The treatment landscape for HCC has evolved since our study was conducted. At the time our study was conducted, TKI therapy was the preferred first-line therapy, now we know that immunotherapy has already moved into the front-line setting. There are many options for randomized studies, the adjuvant setting is open, in combination with the current first-line is open. The refractory setting is actually very wide open for HCC. There are a number of clinical trial designs that are being discussed with the sponsor, and hopefully more to follow. Clearly this approach is exciting and further studies are planned.
Is there anything else about your study you would like to discuss?
Dr. Yarchoan: At a very high level, cancer vaccines are something that have been investigated for a long time and, unfortunately, I think the field has more failures than successes at this point. I mean, really the only approved cancer vaccine is PROVENGE, for prostate cancer, which has marginal efficacy and is barely used in clinical practice at this point. We are in a different era, and we have learned a lot, in part from the COVID pandemic about how vaccines work and what platforms are best. The key innovation has been switching from a sort of cancer associated antigens, things that are on cancer, but also on normal cells and thus do not generate a lot of immunity. Shifting from that to true neoantigens which are totally specific for the cancer cells and therefore induce much stronger immunity because they are not subject to central tolerance. Again, switching to neoantigens, in most cases, requires personalization, because neoantigens are different from tumor to tumor to tumor. This kind of approach has only been made possible because of major technological advancements. Not only in sequencing, the cost of sequencing has fallen precipitously over the last decade, but also with the invention of novel vaccine platforms that allow very rapid personalization both DNA based platforms and RNA based platforms. These platforms really did not exist a decade ago when a lot of vaccines were failing. We are really in a new era. We have a randomized trial from Moderna in the adjuvant setting for melanoma that appears positive and we also have some exciting studies from other platforms including BioNTech in the adjuvant treatment of pancreas cancer. There are a lot of exciting updates for cancer vaccines. What is unique about this particular study is that it is really the first time that this approach has been used for HCC, it is also a different platform than the RNA based platforms that have read out in other tumor types recently. The other studies have predominantly treated adjuvant disease, so the micro metastatic setting, whereas this trial is really in advanced metastatic HCC and it suggests that potentially the role for cancer vaccines may expand beyond the sort of micro metastatic disease setting. For all these reasons, I am certainly excited by this and hope that this becomes an option for patients and holds up in larger studies.
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